Somatic mutations reveal asymmetric cellular dynamics in the early human embryo.
View/ Open
Date
2017-03-30ICR Author
Author
Ju, YS
Martincorena, I
Gerstung, M
Petljak, M
Alexandrov, LB
Rahbari, R
Wedge, DC
Davies, HR
Ramakrishna, M
Fullam, A
Martin, S
Alder, C
Patel, N
Gamble, S
O'Meara, S
Giri, DD
Sauer, T
Pinder, SE
Purdie, CA
Borg, Å
Stunnenberg, H
van de Vijver, M
Tan, BKT
Caldas, C
Tutt, A
Ueno, NT
van 't Veer, LJ
Martens, JWM
Sotiriou, C
Knappskog, S
Span, PN
Lakhani, SR
Eyfjörd, JE
Børresen-Dale, A-L
Richardson, A
Thompson, AM
Viari, A
Hurles, ME
Nik-Zainal, S
Campbell, PJ
Stratton, MR
Type
Journal Article
Metadata
Show full item recordAbstract
Somatic cells acquire mutations throughout the course of an individual's life. Mutations occurring early in embryogenesis are often present in a substantial proportion of, but not all, cells in postnatal humans and thus have particular characteristics and effects. Depending on their location in the genome and the proportion of cells they are present in, these mosaic mutations can cause a wide range of genetic disease syndromes and predispose carriers to cancer. They have a high chance of being transmitted to offspring as de novo germline mutations and, in principle, can provide insights into early human embryonic cell lineages and their contributions to adult tissues. Although it is known that gross chromosomal abnormalities are remarkably common in early human embryos, our understanding of early embryonic somatic mutations is very limited. Here we use whole-genome sequences of normal blood from 241 adults to identify 163 early embryonic mutations. We estimate that approximately three base substitution mutations occur per cell per cell-doubling event in early human embryogenesis and these are mainly attributable to two known mutational signatures. We used the mutations to reconstruct developmental lineages of adult cells and demonstrate that the two daughter cells of many early embryonic cell-doubling events contribute asymmetrically to adult blood at an approximately 2:1 ratio. This study therefore provides insights into the mutation rates, mutational processes and developmental outcomes of cell dynamics that operate during early human embryogenesis.
Collections
Subject
Blood Cells
Humans
Mutagenesis
Cell Lineage
Embryonic Development
Mutation
Mosaicism
Germ-Line Mutation
Genome, Human
Adult
Embryo, Mammalian
Mutation Rate
Language
eng
Date accepted
2017-02-08
License start date
2017-03-22
Citation
Nature, 2017, 543 (7647), pp. 714 - 718
Publisher
NATURE PUBLISHING GROUP